Enhanced Oral Delivery of Low Solubility Drugs using Cocrystal Design

描述（由申请人提供）：开发用于治疗许多人类疾病的新型口服活性治疗剂的主要障碍是这些药物在肠道水环境中的溶解度差。共晶（活性治疗剂与良性分子络合的化学计量分子复合物）代表了一种潜在的有吸引力的新方法，可用于修改和调整溶解度和溶解性，以增强和调节生物利用度。共晶固体已被证明能显著提高水溶解度。然而，对于影响共晶体内性能的关键物理化学和生物因素，如生理上相关的表面活性剂对共晶组分的不同增溶作用，以及活性成分和共晶的不同吸收，人们仍然缺乏了解。因此，迫切需要开发基于机械的策略来指导共晶的表征、选择和配方，从而优化口服给药。在强有力的初步数据的指导下，长期目标是基于共晶提供的固体和溶液化学控制，开发新的有效策略来增强水不溶性药物的口服给药。本应用程序的主要目的是建立决定共晶增溶、溶解和吸收的基本物理化学原理，并建立可用于准确预测体外和体内共晶行为的定量数学关系。中心假设是定量的，基于科学的

DESCRIPTION (provided by applicant): A major impediment to the development of new, orally active therapeutic agents to treat many human diseases is the poor solubility of such agents in the aqueous environment of the intestinal tract. Cocrystals (stoichiometric molecular complexes of an active therapeutic agent complexed with a benign molecule) represent a potentially attractive and new approach that can be used to modify and tailor solubility and dissolution properties to enhance and [modulate] bioavailability. Cocrystalline solids have been shown to profoundly increase aqueous solubility. However, there remains a significant lack of understanding of the key physicochemical and biological factors that influence in vivo performance of cocrystals such as differential solubilization of cocrystal components by physiologically relevant surfactants, and differential absorption of the active ingredient and coformer. There is, therefore, a critical need to develop mechanistic-based strategies to guide cocrystal characterization, selection, and formulation leading to optimized oral delivery. Guided by strong preliminary data, the long-term goal is to develop novel and efficient strategies to enhance the oral delivery of water insoluble drugs based on the solid and solution chemistry control that cocrystals provide. The primary objective in this application is to establish the basi physicochemical principles that dictate cocrystal solubilization, dissolution and absorption, and to establish quantitative mathematical relationships that can be used to accurately predict cocrystal behavior in vitro and in vivo. The central hypothesis is that quantitative, science-based mathematical relationships [that represent the relevant physicochemical processes describing cocrystal, drug and coformer behavior] can be developed to predict cocrystal solubility and dissolution in physiologically relevant media, and application of this knowledge will allow accurate in vivo absorption and bioavailability predictions to be made. To test the central hypothesis and achieve the objectives of this project, three Specific Aims will be pursued: 1) identify key molecular and physicochemical parameters that predict cocrystal solubility in physiologically relevant media, 2) develop predictive diffusion/reaction models of cocrystal dissolution in physiologically relevant media and test in relevant in vitro dissolution systems, 3) assess the oral absorption mechanisms of cocrystal drugs in vitro and in vivo. This research is innovative because it represents a new and substantial departure from current research which focuses exclusively on the physical and chemical properties in the solid state and in simple aqueous solutions. This approach will be effective in integrating biologically relevant components such as surfactants with important oral absorption considerations of both the drug and the associated coformer that make up the cocrystal. This integrated physicochemical and biological model can be expected to lead to more effective and accurate predictions of cocrystal oral absorption rates and ultimately to the development of improved drug delivery systems to treat human diseases.